2-Aminothiazole-5-carboxamides of formula I

wherein,
R1, R2, R3, R4 and R5 defined herein, are useful as kinase inhibitors, including inhibitors of p38 kinase. Inhibiting p38 enzymes in cells results in reduced levels of TNF-α expression, and administering p38 inhibitors in animal models of inflammatory disease has proven that these inhibitors are effective in treating inflammatory and immune conditions. 2-Aminothiazole-5-carboxamides of formula (I) herein, having activity as p38 inhibitors, are described in U.S. patent application Ser. No. 10/773,790, filed concomitantly with the provisional application from which the present application is based, claiming priority to U.S. Provisional application Ser. No. 60/445,410, filed Feb. 6, 2003 (hereinafter the '410 application), both of which are assigned to the present assignee and incorporated herein by reference.
Previous approaches for preparing 2-aminothiazole-5-carboxamides are described in U.S. Pat. No. 6,596,746 (the '746 patent), also assigned to the present assignee, and in the '410 application. The '746 patent describes a process involving treatment of chlorothiazole with n-BuLi followed by reaction with phenyl isocyanates to give chlorothiazolyl benzamides, which are further elaborated to aminothiazolyl benzamide final products after protection, chloro-to amino substitution, and deprotection, e.g.,

The '410 application describes a multi-step process involving first, converting N-unsubstituted aminothiazole carboxylic acid methyl or ethyl esters to bromothiazole carboxylic acid esters via diazotization with tert-butyl nitrite and subsequent CuBr2 treatment, e.g.,

then, hydrolyzing the resulting bromothiazole esters to the corresponding carboxylic acids and converting the acids to the corresponding acyl chlorides, e.g.,

then finally, coupling the acyl chlorides with anilines to afford bromothiazole-benzamide intermediates which were further elaborated to aminothiazole-benzamide final products, e.g.,

Other approaches for making 2-aminothiazole-5-carboxamides include coupling of 2-aminothiazole-5-carboxylic acids with amines using various coupling conditions such as DCC [Roberts et al, J. Med. Chem. (1972), 15, at p. 1310], and DPPA [Marsham et al., J. Med. Chem. (1991), 34, at p. 1594)].
The above methods present drawbacks with respect to the production of side products, the use of expensive coupling reagents, less than desirable yields, and the need for multiple reaction steps. New and efficient processes for preparing 2-aminothiazole-5-carboxamides are desired.
Reaction of N,N-dimethyl-N′-(aminothiocarbonyl)-formamidines with α-haloketones and esters to give 5-carbonyl-2-aminothiazoles has been reported. See Lin, Y. et al, J. Heterocycl. Chem. (1979), 16, at 1377; Hartmann, H. et al, J. Chem. Soc. Perkin Trans. (2000), 1, at 4316; Noack, A. et al; Tetrahedron (2002), 58, at 2137; Noack, A.; et al. Angew. Chem. (2001), 113, at 3097; and Kantlehner, W. et al., J. Prakt. Chem./Chem.-Ztg. (1996), 338, at 403. Reaction of β-ethoxy acrylates and thioureas to prepare 2-aminothiazole-5-carboxylates also has been reported. Zhao, R., et al., Tetrahedron Lett. (2001), 42, at 2101. However, electrophilic bromomination of acrylanilide and crotonanilide has been known to undergo both aromatic bromination and addition to the α,β-unsaturated carbon-carbon double bonds. See Autenrieth, Chem. Ber. (1905), 38, at 2550; Eremeev et al., Chem. Heterocycl. Compd. Engl. Transl. (1984), 20, at 1102.